Chemokine CXCR4 receptor modulators and uses related thereto

This application is a continuation of U.S. application Ser. No. 17/973,336 filed Oct. 25, 2022, which is a continuation of U.S. application Ser. No. 16/487,825 filed Aug. 21, 2019 that granted as U.S. Pat. No. 11,497,744 on Nov. 15, 2022, which is the National Stage of International Application No. PCT/US2018/018973 filed Feb. 21, 2018, which claims the benefit of U.S. Provisional Application No. 62/461,682 filed Feb. 21, 2017, U.S. Provisional Application No. 62/461,690 filed Feb. 21, 2017, U.S. Provisional Application No. 62/461,695 filed Feb. 21, 2017, and U.S. Provisional Application No. 62/461,698 filed Feb. 21, 2017. The entirety of each of these applications is hereby incorporated by reference for all purposes.

The disclosure relates to chemokine CXCR4 receptor modulators and uses related thereto. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising compounds disclosed herein or pharmaceutically acceptable salts or prodrugs thereof. In certain embodiments, the compositions disclosed herein are used for managing CXCR4 related conditions, typically prevention or treatment of viral infections such as HIV or for managing cancer.

As of the end of 2007, an estimated 33 million people worldwide were living with HIV/AIDS, and the Centers for Disease Control and Prevention (CDC) estimates that 1,200,000 U.S. residents are living with HIV infection (, December 2008;, July 2007). Although new infections have decreased in recent years, an estimated 2.6 million new HIV infections occurred worldwide during 2007 and approximately 40,000 new HIV infections occur each year in the United States.

HIV entry within the target cells involves a series of molecular events. The three main steps of virus entry within the cell are: (i) attachment of the virus to the subject cells; (ii) interaction of the virus with the co-receptors; and (iii) fusion of the virus and subject cell membranes. Considering the complexity of the molecular events involved in viral infection, all three of these steps have been considered for drug design. The T-lymphocyte cell surface protein CD4 is the primary receptor involved in the interaction with the viral glycoprotein gp120, but a cellular co-receptor is also needed for the successful entry of the virus within the cell. At least two types of such co-receptors have been identified so far, both of which are chemokine receptors, CCR5 and CXCR4. These chemokine receptors are therefore gateways for HIV entry, determinants of viral tropism and sensitivity.

Compounds targeting viral entry have two advantages over those that target the HIV-1 reverse transcriptase or protease enzymes: entry inhibitors do not depend on efficient cellular uptake or intracellular activation processes to exert their biological effects, and they are highly unlikely to show any cross-resistance with protease inhibitors or reverse transcriptase inhibitors. Viral entry has been validated as a clinically effective pathway for targeted intervention by the first fusion inhibitor, enfuvirtide. Other classes of entry inhibitors under development target the initial binding of viral gp120 to CD4 and the interaction of gp120 with cell surface chemokine receptors that serve as co-receptors for HIV entry (CCR5 or CXCR4). (Westby et al.,2006, 80(10), 4909-4920).

Compounds targeting CXCR4 have been developed primarily for treatment of HIV because CXCR4 is a major co-receptor for T-tropic HIV infection. For example, U.S. Pat. No. 6,429,308 discloses an antisense oligonucleotide to CXCR4 to inhibit the expression of the CXCR4 protein for use as an anti-HIV agent. PCT application publication number WO 2001/56591 describes peptide fragments of viral macrophage inflammatory protein II, which are described as selectively preventing CXCR4 signal transduction and co-receptor function in mediating entry of HIV-I. Additional molecular antagonists of the chemokine CXCR4 receptor are disclosed in PCT application publication numbers WO 2009/121063 and WO 2006/020415 and U.S. Pat. No. 8,969,381.

Studies have shown that CXCR4 interactions also regulate the migration of metastatic cells. Hypoxia, a reduction in partial oxygen pressure, is a micro-environmental change that occurs in most solid tumors and is a major inducer of tumor angiogenesis and therapeutic resistance. Hypoxia increases CXCR4 levels (Staller et al., 2003425: 307-311). Microarray analysis on a sub-population of cells from a bone metastatic model with elevated metastatic activity showed that one of the genes increased in the metastatic phenotype was CXCR4. Furthermore, over-expression of CXCR4 in isolated cells significantly increased the metastatic activity (Kang et al., 20033: 537-549). In samples collected from various breast cancer patients, Muller et al. (2001410: 50-56) found that CXCR4 expression levels are higher in primary tumors relative to normal mammary gland or epithelial cells. These results suggest that the expression of CXCR4 on cancer cell surfaces may direct the cancer cells to sites that express high levels of SDF-I. Consistent with this hypothesis, SDF-I is highly expressed in the most common destinations of breast cancer metastasis including lymph nodes, lung, liver, and bone marrow. Moreover, CXCR4 antibody treatment has been shown to inhibit metastasis to regional lymph nodes when compared to control isotypes that all metastasized to lymph nodes and lungs (Muller et al., 2001410: 50-56).

In addition to regulating migration of cancer cells, CXCR4-SDF-1 interactions may regulate vascularization necessary for metastasis. Blocking either CXCR4/SDF-1 interaction or the major G-protein of CXCR4/SDF-1 signaling pathway (Gα) inhibits VEGF-dependent neovascularization. These results indicate that SDF-1/CXCR4 controls VEGF signaling systems that are regulators of endothelial cell morphogenesis and angiogenesis. Numerous studies have shown that VEGF and MMPs actively contribute to cancer progression and metastasis.

Thus, there is a need to identify CXCR4 antagonists for therapeutic applications in treating or preventing viral infections such as HIV and for treating or preventing cancer.

The disclosure relates to chemokine CXCR4 receptor modulators and their uses in therapeutic and diagnostic applications.

In accordance with a first embodiment of the invention there is provided a compound of Formula (I)

or salts thereof wherein Ris an optionally substituted heterocyclyl, wherein the substituents are selected from one or more, and the same or different R; Ris a hydrogen or an alkyl; Ris selected from the group comprising alkyl, an optionally substituted aminoalkyl and an optionally substituted heterocyclyl; wherein the substituents are selected from one or more, and the same or different R; Ris a hydrogen, optionally substituted alkyl or an optionally substituted heterocyclyl; and Ris selected from the group comprising alkyl, cyloalkyl, halogen, methoxy and triflouromethyl.

Further features of this embodiment provide for Rto be selected from:

for Rto be selected from the group comprising: methyl,

for Rto be H,

CHR, CH═CHCHR, OCHCHR, NHR, N(R),

for Rto be selected from the group comprising H, OH, F, CH, CHCH, CHOCH, CHF, CFNH,

wherein the substituent Rmay be individually and independently mono- or di-substituted onto Rwhere appropriate; and for Rto be selected from the group comprising methyl, ethyl, ethene, propyl, cyclopropyl, fluorine, chlorine, methoxy and trifluoromethyl.

In yet further features of this embodiment Ris selected from the group comprising:

In an exemplary embodiment, the compound of Formula (I) is selected from the group comprising:

In accordance with a second embodiment of the invention there is provided a compound of Formula (II)

or salts thereof wherein Ris H or alkyl, Ris methyl, isopropyl or an amino substituted carbocyclyl; Ris an optionally substituted heterocyclyl; wherein the substituents of Rare selected from one or more and the same or different R; and Ris optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted amino, and wherein the substituents of Rare selected from one or more and the same or different R; and Ris selected from the group comprising methyl, ethyl, isopropyl, cyclopropyl, oxetane, amino, dimethylamino, methylpiperazine, pyridine, pyridinylmethyl, pyrimidine and triflouromethylbenzene; with the proviso that when Ris H and Ris CH, then Ris not:

Further features of this embodiment provide for Rto be selected from the group comprising:

Yet further features of this embodiment provide for Rto be selected from the group comprising:

In an exemplary embodiment of this invention, the compounds of Formula (II) may be selected from the group comprising:

In accordance with a third embodiment of this invention there is provided a compound of Formula (III)

or salts thereof wherein Ris an optionally substituted alkene, which may be E or Z, an optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl or an optionally substituted quaternary carbon; X is C or N, and Ris a hydrogen or a heterocyclyl when X is C or absent when X is N.

Further features provide for Rto be selected from the group comprising:

wherein Y is H, alkyl or halogen; Ris selected from the group comprising H, NH, halogen, CHNHR, and in the case of the carbocycles, aryls and heterocycles Rmay include one or more and the same or different substituent for each cycle; and Ris selected from the group comprising:

Yet further features of this embodiment provide for Rto be selected from the group comprising:

and a CHCHgroup linking the NCHto the tetrahydroquinoline.

In an exemplary embodiment, the compound of Formula (III) is selected from the group comprising:

In accordance with a fourth embodiment of the invention there is provided a compound of Formula (IV)

or salts thereof wherein ring A is an heteroaromatic ring system, with or without a fused benzene ring system, Ris a C1 to C6 alkyl and Z is CH, NH, N or S.

Further features of this embodiment provide for A to be selected from the group comprising: